Project Summary: Arsenic is a common environmental toxicant that threatens over 100 million people globally. In addition to associations with cardiovascular disease, diabetes, and cancer, arsenic is linked to multiple neurocognitive disorders. These epidemiological links are supported by rodent models demonstrating arsenic-mediated disruptions in brain biology. Because of the significant individual and societal burden of mental health disorders, new prevention and treatment approaches are desperately needed. While environmental remediation offers hope for addressing this modifiable risk factor, the extent of exposure and its legacy demand additional means to address arsenic-associated neurocognitive deficits. Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid that is essential for normal neuronal functioning; however, neurons are incapable of synthesizing DHA. Moreover, a central dogma of lipid biology is that the brain DHA pool is established during development and is resistant to later life manipulation. This may explain the curious dichotomy that while low DHA intake is associated with mental health disorders, DHA interventions (as triglyceride [e.g. fish oil]) have disappointed. We propose an alternative hypothesis that triglyceride-DHA (TG-DHA) is poorly suited for DHA delivery across the blood brain barrier (BBB). In contrast, the identification of a specific lysophosphatidylcholine (LPC) transporter at the BBB (Mfsd2a) offers an alternative route for brain DHA enrichment. While endogenous LPC contains very little DHA (LPC-DHA), nutraceutical approaches can enrich plasma LPC-DHA. Indeed, our data indicate that adult brain DHA can be doubled using LPC-DHA, and this enrichment improves learning and memory. This is critical since our data also show arsenic depletes brain DHA. Thus, the central hypothesis of this application is that arsenic-mediated brain DHA depletion causes later life neurocognitive deficits, and targeted rescue with LPC-DHA prevents these adverse outcomes. Importantly, since Mfsda2 is expressed in both the placenta and the BBB, two strategies will be interrogated. In Aim 1, we will use a prevention paradigm to test the hypothesis that developmental DHA supplementation counteracts arsenic-induced DHA depletion and prevents later life cognitive deficits. In Aim 2, we will challenge the dogma of adult brain DHA stasis and interrogate the supposition that intervention after weaning can restore DHA levels and rescue neurocognitive function. In each Aim, the novel LPC-DHA intervention will be compared to the classical TG-DHA approach, and exploratory mechanistic studies will investigate pathways linking arsenic exposure to neurocognitive dysfunction. Given the dual global threats of arsenic and mental health disorders, novel, scalable intervention strategies such as LPC-DHA may hold great promise for reducing significant individual and societal suffering.